Rejuvenating blood stem cells extends lifespan of aged immunocompromised mice

Aging is associated with loss of stem cell regenerative capacity in many tissues. Restoration of aged stem cell function represents a promising strategy to rejuvenate aged tissues and different approaches have been proposed. However, systemic rejuvenation remains a challenge and it is still unclear to what degree stem cells contribute to overall organism lifespan. Here, we demonstrate that a short treatment with CASIN, a Cdc42 inhibitor, improves aged mouse fitness and endogenous skeletal muscle stem cells’ regenerative potential in steady-state and after injury. The same treatment rejuvenates blood stem cells, which show to be significantly youthful as they recover Cdc42 and cell polarity, H4K16ac epigenetic polarity and localization within the bone marrow and improve hematopoietic reconstitution after primary and secondary transplantation restoring lymphoid lineage contribution. Moreover, CASIN treated blood stem cells display a youthful scRNA-seq transcriptome profiling and an improved connectivity across hematopoietic stem and progenitor cell clusters. Importantly, rejuvenated blood stem cells were sufficient to extend the lifespan of aged immunocompromised mice upon transplantation. Overall, our data support that blood stem cells and the hematopoietic system exert a central and broad function in the decline of organism fitness with aging, providing the proof-of-concept evidence that increasing the regenerative potential of endogenous aged somatic stem cells might represent an important strategy for improving health- and lifespan in the elderly.